5-phenyl-2-piperidones and 5-phenyl-2-thiopiperidones

ABSTRACT

NOVEL 5-PHENYL-2-PIPERIDONE AND 5-PHENYL-2-THIOPIPERIDONE COMPOUNDS AND THE PROCESSES FOR PREPARING THE SAME ARE DISCLOSED. THE ADDITION THE INVENTION CONCERNS PIPERIDONES AND THIOPIPERIDONES WHICH EXHIBIT ANTI-INFLAMMATORY PROPERTIES AND ALSO POSSESS AN EFFECTIVE DEGREE OF ANTIPYRETIC AND ANALGESIC ACTIVITY.

United States Patent Office 3,814,771 Patented June 4, 1974 3,814 771S-PHENYL-Z-PIPERIDO NES AND S-PHENYL- Z-THIOPIPERIDONES Tsung-Ying Shen,858 Willow Grove Road, and Bruce E. Witzel, 206 N. Euclid Ave., both ofWestfield, NJ. 07090 No Drawing. Continuation-impart of application Ser.No. 91,175, Nov. 19, 1970, now Patent No. 3,718,743, which is acontinuation-in-part of abandoned application Ser. No. 808,660, Mar. 19,1969. This application July 19, 1972, Ser. No. 273,233

Int. Cl. C07d 29/36 US. Cl. 260-293.73 3 Claims ABSTRACT OF THEDISCLOSURE Novel 5-phenyl-2-piperidone and 5-phenyl-2-thiopiperidonecompounds and the processes for preparing the same are disclosed. Inaddition the invention concerns piperidomes and thiopiperidones whichexhibit anti-inflammatory properties and also possess an effectivedegree of antipyretic and analgesic activity.

This application is a continuation of pending United States applicationSer. No. 91,175, filed Nov. 19, 1970, which was issued to Pat. No.3,718,743 on Feb. 27, 1973, which application is a continuation-in-partof United States application Ser. No. 808,660, filed Mar. 19, 1969, nowabandoned.

This invention relates to a novel class of 5-phenyl-2- piperidones andthiopiperidones and derivatives thereof which are useful in thetreatment of inflammation and which also exhibit potent analgesic andantipyretic actviity. The invention further relates to pharmaceuticalcompositions containing said materials and methods of treatinginflammation, pain and fever.

The present invention embraces the novel compounds having the structuralformulae as shown in FIGS. Ia and where W is hydrogen, halogen (such asfluoro, chloro, bromo,

etc.), halo alkyl (such as C1 amino, dialkylamino (preferablydiloweralkylamino such as dimethylamino, diethylamino, methylethylamino,etc.), dialkylaminoalkyl (preferably diloweralkylaminoloweralkyl such asdimethylaminomethyl, diethylaminomethyl, etc.), carboalkoxyalkyl(preferably carboloweralkoxyloweralkyl such as carbomethoxymethyl,carboethoxymethyl, etc.)

and hydroxy; W can be substituted at the 3, 4, 5 or 6- positions; and

X and Y are each hydrogen, alkyl (preferably loweralkyl as methyl,ethyl, propyl, etc.), halogen (such as fiuoro, chloro, bromo, etc.),haloalkyl (preferably haloloweralkyl such as fiuoromethyl,trichloromethyl, trifluoromethyl, etc.), aryl (preferably phenyl,naphthyl, substituted phenyl, such as tolyl, halophenyl, alkoxyphenyl,etc.), nitro, amino, acylamino (such as acetylamino, etc.), acyl (suchas acetyl, propionyl, benzoyl, etc.), carboxy, carboalkoxy (preferablycarboloweralkoxy such as carbomethoxy, carboethoxy, etc.), carbamyl,dialkylsulfamyl (preferably diloweralkylsulfarnyl such asdimethylsulfamyl), alkylamino (prefearbly loweralkylamino such asmethylamino, ethylamino, etc.), and dialkylamino (preferablydiloweralkylamino such as dimethylamino, diethylamino, etc.),alkylmercapto (preferably loweralkylmercapto, such as methylmercapto,etc.), alkylsulfinyl (preferably loweralkylsulfinyl, such asmethylsulfinyl, etc.), alkylsulfonyl (preferably loweralkylsulfonyl,such as methylsulfonyl, etc.); X and Y can be substituted at the 2, 3,4, 5 and 6-positions;

with the proviso that W, X, Y and R must not be all hydrogen at the sametime, and when R is alkyl, W, X or Y must be other than hydrogen andwhen W is halogen, dialkylamino or dialkylaminoalkyl, R, X or Y must beother than hydrogen.

In its more preferred aspects, this invention relates to the class ofchemical compounds having the structural formulae as shown in FIGS. Iaand lb where R is hydrogen; W is hydrogen or halogen; and X and Y arehydrogen, halogen, haloalkyl, nitro, alkylamino and alkyl.

The invention further relates to 5-phenyl-2-piperidones andthiopiperidones as represented by Formulas Ila and 11b which are usefulin the treatment of inflammation, pain and fever and are components ofpharmaceutical compositions that are utilized in such treatment:

x Y X Y 11a IIb where R is hydrogen, alkyl (preferably lower alkyl suchas methyl, ethyl, propyl, etc.), alkenyl (preferably lower alkenyl suchas vinyl, allyl, methallyl, etc.), alkynyl (preferably lower alkynylsuch as ethynyl, methylbutynyl, etc.), aralkyl (preferably arloweralkylsuch as benzyl, phenethyl, etc.), aralkenyl (preferably arloweralkenylsuch as phenylpropylenyl, phenylbutylenyl, etc.), aryl (preferablyphenyl) or substituted phenyl (such as tolyl, halophenyl, anisyl, etc.),acyl (such as acetyl, propionyl, benzoyl, etc.) and dialkylaminoalkyl(preferably diloweralkylaminolower alkyl, such as diethylaminoethyl,etc.)

W is hydrogen, halogen (such as fiuoro, chloro, bromo,

etc.), halo alkyl (such as C1 alkyl (preferably lower alkyl such asmethyl, ethyl, propyl, etc.), amino, dialkylamino (preferablydiloweralkylamino such as dimethylamino, diethylamino, methylethylamino,etc.), dialkylarninoalkyl (preferably diloweralkylaminoloweralkyl suchas dimethylaminomethyl, diethylaminomethyl, etc.), aryl (preferablyphenyl or substituted phenyl), carboalkoxy (preferably carboloweralkoxysuch as carbomethoxy, carboethoxy, etc.), carboalkoxyalkyl (preferablycarboloweralkoxyloweralkyl such as hydroxy; W can be substituted at the3, 4, 5 or 6- carbomethoxymethyl, carboethoxymethyl, etc.),. andpositions; and

X and Y are each hydrogen, alkyl (preferably loweralkyl such as methyl,ethyl, propyl, etc.), halogen (such as fiuoro, chloro, bromo, etc.),hydroxy, alkoxy (preferably lower alkoxy such as methoxy, ethoxy,propoxy, etc.), haloalkyl (preferably haloloweralkyl such asfluoromethyl, trichloromethyl, trifluoromethyl, etc.), aryl (preferablyphenyl, naphthyl, substituted phenyl, such as tolyl, halophenyl,alkoxyphenyl, etc.), nitro, amino, acylamino (such as acetylamino,etc.), acyl (such as acetyl, propionyl, benzoyl, etc.), carboxy,carboalkoxy (preferably carboloweralkoxy such as carbomethoxy,carboethoxy, etc.), carbamyl, dialkylsulfamyl (preferablydiloweralkylsulfamyl such as dimethylsulfamyl), alkylamino (preferablyloweralkylamino such as methylamino, ethylamino, etc.) and dialkylamino(preferably diloweralkylamino such as dimethylamino, diethylamino,etc.), alkylmercapto (preferably loweralkylmercapto, such asmethylmercapto, etc.), alkylsulfinyl (preferably loweralkylsulfinyl,such as methylsulfinyl, etc.), alkylsulfonyl (preferablyloweralkylsulfonyl, such as methylsulfonyl, etc.): X and Y can besusbstituted at the 2, 3, 4, 5 and 6-positions.

In its more preferred aspects, this invention relates to the class ofchemical compounds having the structural formulae as shown in FIGS. 11aand 11b where R is hydrogen; W is hydrogen, halogen or alkyl; and X andY are hydrogen, halogen, alkoxy, haloalkyl, nitro, alkylamino and alkyl.

Representative compounds of this invention are as follows:

5- (p-nitrophenyl) -2-piperidone 5- (p-chlorophenyl) -2-piperidone 5-o-chlorophenyl) -2-thiopiperidone 5- o-tolyl) -2-piperidone 5- (o-tolyl)-2-thi0piperidone 5- p-fiuorophenyl) -2-piperidone 5- (p-fluorophenyl-2-thiopiperidone 5- (p-aminophenyl -2-piperidone 5 m-chlorophenyl)-5-carboethoxy-2-pip eridone 5- (p-methoxyphenyl) -2-piperidone 5-o,o'-dichlorophenyl) -2-piperidone 5- (p-methoxyphenyl) -3-methyl-1-acetyl-2-thiopiperidone 5- (p-nitrophenyl)l-benzyl-2-piperidone 5- p-biphenylyl) -5-methyl-2-thiopiperidone5-phenyl- 1 -acetyl-2-piperidone 5 -phenyl-3-chloro-1-methyl-2-thiopiperidone.

The piperidones and thiopiperidones of the invention possess a highdegree of anti-inflammatory, analgesic and antipyretic activity. Theyare of value in the treatment of arthritic and dermatological disordersor like conditions responsive to anti-inflammatory drugs. In generalthey are indicated for a wide variety of conditions where one or more ofthe symptoms of infiamation, fever and pain are manifested. Exemplary ofsuch conditions are rheumatic diseases, for example, rheumatoidarthritis, osteoarthritis, and other degenerative joint diseases,psoriatic arthritis, ankylosing spondylitis, gout, and rheumatic fever;soft-tissue rheumatism, for example, tendinitis, periarthritis, andperiostitis; acute muscular rheumatism, for example, sciatica and thelike; treatment of pain after fractures, pain and inflammationassociated with dental surgery, and the like, human and veterinarydisease conditions exhibiting the foregoing symptoms requiring the useof an anti-inflammatory, analgesic and/or anti-pyretic pharmaceuticalcomposition.

[For these purposes the compounds of the invention may be administeredorally, topically, parenterally, by inhalation spray or rectally informulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, dogs,cats, etc., the compounds of the invention are effective in thetreatment of humans.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide a pharmaceutically elegant andpalatable preparation. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be,for example, inert diluents, such as calcium carbonate, sodiumcarbonate, lactose, calcium phosphate or sodium phosphate; granulatingand disintegrating agents, for example, maize starch, or alginic acid;binding agents, for example starch, gelatine or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearateabove or with a wax may be employed.

Formulations for oral use may also be presented as hard gelatinecapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatine capsules wherein the active ingredient is mixed withwater or an oil medium, for example arachis oil, peanut oil, liquidparafiin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium agmate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturallyocc urring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol mono-oleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyoxyethylene sorbitanmono-oleate. The said aqueous suspensions may also contain one or morepreservatives, for example ethyl, or npropyl, p-hydroxy benzoate, one ormore coloring agents, one or more flavoring agents, and one or moresweetening agents, such as sucrose, saccharin, or sodium or calciumcyclamate.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example besswax, hardparafiin or cetyl alcohol. Sweetening agents, such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oils, or a mineral oil, for example liquidparafiin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soya bean lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan mono-oleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan mono-oleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, sorbitol or sucrose. Such formulations may also contain ademulcent, a preservative and flavoring and coloring agents.

The pharmaceutical compositions may be in the form of a sterileinjectable preparation, for example as a sterile injeetablc aqueous oroleagenous suspension. This suspension may be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterallyacceptable diluent or solvent, forexample as a solution in 1:3-butane diol. Among the acceptable vehiclesand solvents that may be employed are water, Ringers solution andisotonic sodium chloride solution. In addition, sterile, fixed oils areconventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic monoordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectibles.

For parenteral administration aqueous fluid unit dosage forms can beprepared. In preparing the parenteral form, a measured amount of activeingredient is placed in a vial, and the vial and its contents aresterilized and sealed. An accompanying vial of sterile water is providedas a vehicle to form a suspension prior to administration.Advantageously, the sterile water can have dissolved therein a localanesthetic and a buffering agent. Parenteral aqueous solutions can bemade by preparing a suitable pharmaceutically-acceptable salt of theactive ingredient such as the acetate, citrate, tartrate, maleate,lactate and the like.

Alternatively, a parenteral suspension can be prepared by suspending theactive ingredient in a parenterally-acceptable vegetable oil with orwithout additional adjuvants, and sterilizing after filling into vials.

For veterinary oral use the active ingredient is conveniently preparedin the form of a food premix. The food premix can comprise the activeingredient in admixture with an edible pharmaceutical diluent of thetype previously mentioned such as starch, oatmeal, flour, calciumcarbonate, talc, dried fish meal, and the like. The prepared premix isthen conveniently added to the regular feed, thereby providingmedication to the animal in the course of feeding.

The compounds of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jelies solutions or suspensions,etc. containing the anti-infiamatory agents are employed.

Dosage levels of the order of 0.5 to 100 mg. per kilogram of body weightper day are useful in the treatment of the above indicated conditions.Accordingly, inflammation is efiectively treated and anti-pyretic andanalgesic activity manifested by the administration from about .5 to 100milligrams of the compound per kilogram of body weight per day.Advantageously oral administration of from about 2 mg. to about 50 mg.per kilogram of body weight and especially from about 4 mg. to about 20mg./ kg. per daily dosage produce highly effective results. Comparativedosages are used in parenteral, rectal and topical administration.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration of humans may containfrom 5 mg. to 5 grams of active agent compounded with an appropriate andconvenient amount of carrier material which may vary from about 5 toabout percent of the total composition. Dosage unit forms will generallycontain between from about 25 mg. to about 500 mg. of active ingredient.

The term unit dosage form as used in the specification and claims refersto physically discrete units suitable as unitary dosages for humansubjects and animals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical diluent, carrier orvehicle. The specifications for the novel unit dosage forms of thisinvention are dictated by and directly dependent on (a) the uniquecharacteristics of the active material and the particular therapeuticeffect to be achieved, and (b) the limitations inherent in the art ofcompounding such active material for therapeutic use in humans andanimals, as disclosed in detail in this specification, these beingfeatures of the present invention.

Examples of suitable unit dosage forms in accord with this invention aretablets, capsules, pills, troches, powder packets, granules, wafers,cachets segregated multiples of any of the foregoing and other forms asherein described.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration rate of excretion, drug combination and the severity ofthe particular disease undergoing therapy. In general, the dosageregimen in carrying out the methods of this invention is that whichinsures maximum therapeutic response until improvement is obtained andthereafter is the minimum effective level which continues to providerelief.

The 5-phenyl-2-piperidones and 5-phenyl-2-thiopiperidones of thisinvention are conveniently prepared by the following methods.

When an acrylic acid ester or a substituted acrylate is condensed usingMichael reaction conditions with a benzyl or substituted benzyl cyanide,the corresponding 7- cyano- -phenyl butyrate (IV) is formed. Catalyticreduction of the nitrile affords the A-amino-y-phenyl valerate (III)which rapidly undergoes intermolecular reaction with the ester group toobtain the desired S-phenyl-Z-piper' idones *(IIa); activation of thel-nitrogen followed by treatment with an alkylating or acylating agentresults in N-substituted 5-phenyl-2-piperidones (Ia).

When the synthesis of products with various substituents is desired, theMichael condensation is carried out with the appropriately substitutedstarting materials. Thus, if

the (p-chlorophenyl)-3-methyl-2-piperid0ne is desired,

The following reaction equations illustrate this method of preparation:

il l here W, X, Y and R are as defined above and R is alkyl or aralkyl.

(a) The Michael condensation is carried out in a suitable solvent(preferably a polar solvent, such as ethanol, dioxane, dimethoxyethane,etc.) in the presence of a strong base such as sodium alkoxide, tritonB, etc.

(b) Reduction of the nitrile is carried out catalytically in a polarsolvent. It is preferable to use Raney nickel in an alcohol under500-3000 p.s.i.

(c) Upon heating the reduction product between 30 and 125 C. ringclosure takes place.

(d) Reacting with a strong base such as sodium hydride in an inertatmosphere activates the l-nitrogen. Addition of an alkylating oracylating agent, such as an aliphatic tosylate or halide or an alkanoicacid anhydride or halide, or a benzoyl halide results in theN-substituted products.

A further method of preparation involves the reduction of thecorresponding S-phenyl-Z-pyridone compounds. When a 5-amino-2-halopyridine is diazotized in the presence of benzene or a substitutedbenzene compound, the corresponding 5-phenyl-2-halo pyridine (V1) isformed, which upon hydrolysis gives the 5-phenyl-2- [1H]-pyridones (V)selecti've reduction of the pyridine ring results in the formation of5-phenyl-2-piperidone compounds (II) which can then be alkylated oracylated as above to prepare the desired N-substituted 5-pheny1-2-piperidone (I) products. The following reaction equation illustratesthis method of preparation:

(e) The diazotization of the 2-ehloro-5-amino pyridines is carried outwith or without an inert solvent in the presence of amyl nitrite and thesubstituted benzene with heating. Other nitrosating agents may be usedin place of amyl nitrite.

(f) Hydrolysis of 2-halo pyridine compounds can be carried out in thepresence of a strong base or by the use of a metal acetate in aceticacid.

(g) Selective catalytic reduction of the pyridone ring with a metalcatalyst in the presence of hydrogen gives the 5-phenyl-2-piperidones.

(h) Reacting with a strong base such as sodium hydride in an inertatmosphere activates the l-nitrogen. Adtion of an alkylating oracylating agent such as an all: phatic tosylate or halide or an alkanoicacid anhydride, or halide, or a benzoyl halide results in theN-substituted products.

The 5-phenyl-2-thiopiperidone (lb) of this invention can be preparedfrom the corresponding 5-phenyl-2-piperiv dones by heating with P 8 Thereaction can be carried out either on those compounds which areunsubstituted at the l-position (Ila) which can then be l-alkylated orl-acylated to the desired compounds (lb), or the products can beprepared from those compounds which are already substituted at the 1-position (Ia). These reactions are represented by the followingequations:

Appropriately desired end products having various W, X and Ysubstituents can be prepared at various stages of the synthesis usingsuitable reactions in order to convert one group to another, thus, forexample, using conventional methods, a halogen group can be treatedunder Rosenmund Von Braun conditions to the nitrile compound which inturn can be hydrolyzed to a carboxy. A nitro can be reduced to an aminogroup and a hydroxy compound can be prepared by demethylation of amethoxy substitutent. Mercapto groups can be prepared from conventionaldiazotization techniques.

The starting materials of this invention, namely, the benzyl-cyanidesand 2-halo-5-amino pyridines are well known in the art.

The intermediate compounds of this invention are not only useful inpreparing the end products of this invention but .do'themselves exhibitanti-inflammatory activity and are therefore useful in the treatment ofthe same disorders.

The following are a group of detailed examples which show thepreparation of desired compounds of this invention. They are to beconstrued as illustrations of the invention and not as limitationsthereof.

EXAMPLE 1 Methyl -cyano-y-Ip-chlorophenyl) butyrate To 91 g. ofp-chlorobenzyl cyanide and 6 ml. of Triton B in 360 ml. of dioxane isadded 38.7 g. of methyl acrylate over an 80-minute period, while keepingthe temperature below 40 C. The reaction mixture is then cooled to roomtemperature, allowed to stir for 15 hours, and concentrated to aresidue. The crude product is partition separated with 800 ml. of ether,30 drops of acetic acid and 300 ml. of water. The ether layer is washedwith water, dried over sodium sulfate, and distilled to obtain methyl'y-cyano-q-(p-chlorophenyl)-butyrate (B.P. 170-l73 C./3 mm).

EXAMPLE 1a When an equimolar amount of the nitriles of Table I below aresubstituted for p-chlorobenzyl cyanide in the procedure of Example 1,the corresponding *y-cyano-y- (substituted phenyl) butyrate of Table IIbelow is obtained.

Table I benzyl cyanide p-fluoorbenzyl cyanide o-fluorobenzyl cyanidem-fiuorobenzyl cyanide o-chlorobenzyl cyanidem-chloro-(acarboethoxy)-benzyl cyanide p-methoxybenzyl cyanideo-methoxybenzyl cyanide m-methoxybenzyl cyanide petrifiuoromethylbenzylcyanide p-dimethylaminobenzyl cyanide p-methylaminobenzyl cyanidep-phenyl-e-methyl benzyl cyanide p-nitrobenzyl cyanide a-naphthylmethylcyanide fl-naphthylmethyl cyanide o-rnethylbenzyl cyanide m-methylbenzylcyanide p methylbenzyl cyanide 2,6-dichlorobenzyl cyanidepentafluorobenzyl cyanide p-a'ce tylbenzyl cyanide p-carbomethoxy-u-phenyl benzyl cyanide p-acetamidobenzyl cyanidep-dimethylsulfamylbenzyl cyanide 2 -methyl-4-chlorobenzyl cyanide3,4-dimethoxybenzyl cyanide 1 0 Table 11 methyl'y-cyano-y-phenylbutyrate methyl 'y-cyano-y-(p-fiuorophenyl)butyratemethyl 'y-cyano-y-(o-fiuorophenyl)butyrate methyl-cyano-v-(m-fiuorophenyl)butyrate methyl-cyano-qr(o-chlorophenyDbutyrate methyl a-carboethoxy-y-cyanoy-(m-chlorophenyD- butyrate methyl 'y-cyano--y-(p-methoxyphenyl)butyratemethyl 'y-cyano-q-(p-trifiuoromethylphenyl) butyrate methyl-cyano-y-(p-dimethylaminophenyl)butyrate methyl-cyano-y-(p-methylaminophenyl)butyrate methylu-methyl-y-cyano-y-(p-biphenylyl)butyrate methyl 'y-cyano-v-(p-nitrophenyDbutyrate methyl 'y-cyano-y-(a-naphthyDbutyrate methyl'y-cyano-y-(o-methylphenyl)butyrate methyl 'y-cyano--(2,6-dichloropheny1)butyrate methyl -cyano-y-(pentafluorophenyl)butyrate methyl -y-cyano-'y-(p-acetylphenyl)butyratemethyl a-phenyl-y-cyano-y- (p-carbomethoxyphenyD- butyrate methyl'y-cyano-y-(p-acetamidophenyl)butyrate methyl'y-cyano-y-p-dimethylsulfamylphenyl)butyrate methyly-cyano-q-(2-methyl-4-chlorophenyl)butyrate methyl'y-cyano-y-(3,4-dimethoxyphenyl)butyrate EXAMPLE lb When an equimolaramount of the substituted acrylates of Table III below is used in theprocedure of Example 1 with the desired nitrile of Table I, Example 1A,the corresponding 'y cyano 7 (substituted phenyl) substituted butyrateis formed. A representative list of these products is shown in Table IVbelow.

Table III methyl a-methyl acrylate ethyl a-methyl acrylate methyl0:,B-difl1fithYl acrylate methyl a-dimethylaminoacrylate ethylu-dimethylaminoethylacrylate methyl B-phenylacrylate methyla-phenylacrylate methyl crotonate Table IV 5-(p-chlorophenyl)-2-piperidone methyl A-amino-y- (p-chlorophenyD-valerateTo 11.9 g. of methyl 'y-cyano-7-(p-chlorophenyl)- butyrate and 1 g. ofplatinum oxide, is added 40 ml.

of glacial acetic acid. This is agitated at room temper" ature under 40p.s.i. in a hydrogen atmosphere. The reaction mixture is filtered andconcentrated in vacuo to a colorless oil.

-(p-ch1orophenyl)-2-piperidone EXAMPLE 2a 5-(o-methylphenyl)-2-piperidone To 13 g. of methyl'y-cyano-y-(o-methylphenyl)butyrate and 0.5 g. of Raney nickel is added15 ml. of ethanol. This is reacted at 150 C. under 2000 psi. in ahydrogen atmosphere. The reaction mixture is filtered, rinsed withethanol and concentrated in vacuo to a solid residue. The residue isdissolved in benzene, filtered and concentrated to a volume of about 65ml. hot petroleum ether is then added to 125 ml. total volume. This thenallowed to cool and the product 5-(o-methylphenyl)-2-piperidone (M.P.140.5-143" C.) is collected.

EXAMPLE 2b When an equimolar amount of each of the fcyano-y-(substituted phenyl)butyrate compounds of Tables II and IV, Example 1,are used in place of methyl 'y-cyano-y-(pchlorophenyl)butyrate in theprocedures of Example 2, the corresponding 5-substitutedphenyl-Z-piperidone is formed. A representative list of these productsis shown in Table 1 below.

Table I S-phenyl-Z-piperidone 5- (p-fluorophenyl)-2-piperidone5-(o-fluorophenyl)-2-piperidone 5-(m fluorophenyl)-2-piperidone5-(o-chlorophenyl)-2-piperidoneS-(m-chlorophenyl)-5-carboethoxy-2-piperidone 5-(p-methoxyphenyl)-2-piperidone 5- (p-trifluoromethylphenyl)-2-piperidone5- (o-trifluoromethtylphenyl)-2-piperidone5-(m-trifluoromethylphenyl)-2-piperidone 5-(p-dimethylaminophenyl)-2-piperidone5-(p-methylaminophenyl)-2-piperidone5-(p-biphenylyl)*5-methyl-2-piperidone 5- (o-naphthyl) -2-piperidone5-(a-naphthyl)-2-piperidone 5-(o-methylphenyl)-2-piperidone5-(2,6-dichlorophenyl)-2-piperidone S-(p-acetylphenyl)-2-piperidoneS-(p-carbomethoxyphenyl)-5-phenyl-2-piperidone 5- p-carboxyphenyl)-2-piperidone S-(p-acetamidophenyl)-2-piperidone 5p-dimethylsulfamylphenyl) -2-piperidone5-(2-methyl-4-chlorophenyl)-2-piperidone5-(3,4-dirnethoxyphenyl)-2-piperidone 3-methyl-S-phenyl-Z-piperidone3-methyl-5- (o-methylphenyl piperidone 3-methyl-5-(p-chlorophenyl)piperidone 3 -methyl-5 (2,6-diohlorophenyl piperidone3,4-dimethyl-5-(o-methylphenyl)piperidone3-dimethylamino-S-phenyl-Z-piperidone I3-dimethylaminoethyl-S-phenyl-2-piperidone4-phenyl-5-(o-methylphenyl)-2-piperidone 3-phenyl-5-(o-methylphenyl)-2-piperidone 3,4-dimethyl-5-(p-chlorophenyl)-2-piperidone3,4-dimethyl-5-(o-methylphenyl)-2-piperidone 3-methyl-5-(2,6-dichlorophenyl)-2-piperidone3-methyl-5-(p-methoxyphenyl)-2-piperidone3-methyl-5-(2-methyl-4-chlorophenyl)-2-piperidone 12 3,4-dimethyl-5-(p-biphenylyl) -2-piperidone3,4-dimethyl-5-(o-chlorophenyl)-2-piperidone3-methyl-5-(3,4-dimethoxyphenyl)-2-piperidone H XAMPLE 3 P PY Y)-2-Piperidone To 5.23 g. of 5-(p-chlorophenyl)-2-piperidone dissolvedin 100 ml. of dimethylformamide is added- 1.25 g. of sodium hydride.This is heated-at 45 C. for 2 hours and ice-cooled. To the reactionmixture is then added 3.57 g. of 1-bromo-2-propyne. The reaction mixtureis then stirred at room temperature for 10 hours. 200 m1. of ice-wateris then added, followed by 3 ml. of 2.5 N HCl. The solid is thenfiltered and washed with ice-water. The product is recrystallized toobtain pure S-(p-chlorophenyl)-1-(2-propyny1)-2-piperidone.

EXAMPLE 3a Table H 5- (p-chlorophenyl) l-methyl-Z-piperidone 5(pehlorophenyl)-1-(2-buteny1) -2-piperidone 5-(p-chlorophenyl)-1-(4-pentenyl)-2-piperidone 5 p-chlorophenyl)-1-methallyl-2-piperidone 5- (p-chlorophenyl )-1- (3-pentynyl)-2-piperidone 45 i 5- (p-chlorophenyl)-1-benzyl-2-piperidone 5-(p-chlorophenyl)-1-phenethyl-2-piperidone 5-(p-chlorophenyl)-1-benzoy1-2-piperidone 5- (p-chlorophenyl)-1-acetyl-2-piperidone 5- (p-chlorophenyl1-cyclopropylcarbonyl-Z-piperidonieS-(p-chlorophenyl)-l-(3-phenyl-2-propenyl) 2- piperidone 5p-chlorophenyl)-1-diethylaminoethyl-2-piperidone EXAMPLE 3 Following theprocedure of Example 3 but substitub' ing an equimolar amount of thereactant of Table 11, Example 3a, in place of 1-bromo-2-propyne and anequimolar amount of the 2-piperidones of Table I, 'Example 2, andExamples 7 and 9, in place of S-(p-chlorophenyl)-2-piperidone, thecorresponding 1-substituted-2- piperidone products are obtained. Arepresentative list of these products is shown in Table III below. 7

Table III 1 5 -phenyl-1-(2-propenyl)-2-piperidone5-phenyll-benzyl-Z-piperidone 5-pheuyl-l-methallyl-Z-piperidone5-phenyl-l-benzoyl-Z-piperidone wS-phenyl-l-(3-phenyl-2-propenyl)-2-piperidone 1 .3 p-nitrophenyl-l-methallyl-Z-piperidone 5- (p-nitropheny1)-1- (p-chlorobenzoyl)-2-piperidone 5- (2,6-dichloropheny1) -1-methallyl-3-chloro-2-piperidone 5 p-fiuorophenyl 1-diethylaminoethyl-Z-piperidone 5-(p-acetamidophenyl l-phenethyl-Z-piperidone 5-(p-dimethylaminophenyl)-1-benzoyl-2piperidone S-(p-methoxyphenyl -1-(p-chlorobenzoyl)-2-piperidone S-(p-dimethylaminophenyl)-1-(p-chlorobenzoyl)-2- piperidone 5- a-naphthyl -1-methyl-2-piperidone5- (o-methylphenyl)-1-acetyl-4-chloro-2-piperidone 5- (o-methylphenyl)-1-methy1-4-methyl-Z-piperidone S-phenyl-l-acetyl-3-methyl-2-piperidone5-phenyl-1-acetyl-3 -dimethylamino-Z-piperidone S-(p-nitrophenyl)-1-benzyl-3 ,4-dimethyl-2-piperidone 5- (p-fiuorophenyl) I-(Z-butenyl)-3-carboxy-2- piperidone EXAMPLE 3 C l-phenyl-S- (o-tolyl) -2-piperidoneTo 0.025 m. of 5-(o-tolyl)-2piperidone dissolved in 100 ml. of benzeneis added 1.25 g. of sodium hydride. The reaction mixture is heated to ca45 C. for 8 hours, and then at room temperature for 15 hours. Themixture is then centrifuged and the gel-like N-sodio compound dried inan Abderhalden. This is then added to 5 ml. of iodobenzene and 0.3 g. ofcopper metal and heated rapidly to 120i2 C. for 35 minutes and thenallowed to cool slowly to room temperature. Dry chloroform is then addedto a volume of about 50 ml., this is then allowed to stir, filtered andwashed with chloroform. The chloroform is evaporated to dryness and theresidue chromatographed on 300 g. of silica gel using -80%etherpetroleum ether to obtain l-phenyL-S-(o-tolyl)-2-piperidone.

In a similar manner the 5-aryl-2-piperidone of this invention may beconverted to the desired l-phenyl-S- aryl-2-piperidone.

EXAMPLE 4 5- (o-tolyl -2-chloropyridine 2-chloro-5-aminopyridine (5 g.)in 50 ml. of anhydrous toluene is added dropwise over /2 hour to 150 ml.of toluene to which has just been added 8 ml. of isoamyl nitrite, andwhich is held at 5055 C. The mixture is heated to 75 C. over 2 hours.The solution is decanted from any tars which have precipitated and theexcess toluene is removed in vacuo. Distillation of the residue yieldsS-(o-tolyl)-2-chloropyridine, and lesser amounts of the mand p-tolylisomers.

EXAMPLE 4A Similarly, when the toluene in the above reaction is replacedby benzene, anisole, benzonitrile, xylene, nitrobenzene, fiuorobenzene,benzotrifluoride, naphthylene, o-, mand p-dichlorobenzenes,hydroquinone, dimethyl ether, yeratrole or biphenyl, the corresponding2-chloro-5-arylpyridine is obtained. The products are mixtures of theisomeric arylpyridines and the isomers are separated by fractionaldistillation and/or column or vapor phase chromatography. In this Waythere are obtained:

2-chloro-5-phenyl pyridines 2-chloro-5-(o-, mandp-methoxyphenyl)pyridines 2-chloro-5-(o-, mand p-cyanophenyl)pyridines2-chloro-5-(o-, mand p-xylenyl)pyridines 2-chloro-5-(o-, mandp-nitrophenyl)pyridines 2-chloro-5-(o-, mand p-fiuorophenyl)pyridines2-chloro-5-(o-, mand p-trifiuoromethyl)pyridines 2-chloro-5-(aandB-naphthyDpyridines 2-chloro-5-(o,mm,po,oo,p'- m,mand o,m-

chlorophenyl) pyridines 2-chloro-5-(o,mm,po,o'- o,p'- m,mandemdimethoxyphenyl pyridines 2-chloro-5-(o,mm,po,oo,p'- m,m'- and o,m'-

dimethoxyphenyl)pyridines 2-chloro-5-(o-, mand p-biphenylyl)pyridinesEXAMPLE 4B When 2-chloro-5-aminopyridine is replaced in Examples 4 and4A by substituted 2-chloro-S-amino-pyridines, the correspondingsubstituted 5-phenyl or S-substituted phenyl-Z-chloropyridine productsare obtained.

In this way there are obtained the following:

2-chloro-3-methyl-5-phenylpyridine 2-chloro-4-methyl-S-phenylpyridine2-chloro-3-methyl-5-(o-, mand p-methylphenyl) pyridine2-chloro-3-dimethylarnino-5-(o-, mand p-methylphenyl pyridine2-chloro-4-diethylaminoethyl-S-(o-, mand p-nitrophenyl)pyridine2-chloro-3-phenyl-S- (o-methylphenyl pyridine2-chloro-3-carbomethoxymethyl-5- (ct-naphthyl) pyridine EXAMPLE 55-(o-tolyl)-2-[1H]pyridone A mixture of 0.01 moles of2-chloro-5-(o-tolyl)pyridine, 35 ml. of 20% sodium hydroxide and 50 ml.of dimethylformamide are heated at C. for eight hours.

The reaction mixture is cooled, neutralized with dilute hydrochloricacid, concentrated in vacuo, taken up in hot chloroform, and washed withwater. The chloroform extract is dried over sodium sulfate andconcentrated. The residue is chromatographed on 250 g. of silica gel andeluted with methanol/methylene chloride (0-75%) to give5-(o-tolyl)-2[1H]pyridone.

EXAMPLE 5A Similarly, when the other substituted2-chloro-5-phenylpyridines from Examples 4A and 4B are used in place of2-chloro-5-(o-tolyl)pyridine, the corresponding 2-pyridone is obtained.In this way there is obtained:

EXAMPLE 6 5-(o-to1yl)-2-piperidone To 0.01 mole of5-(o-tolyl)-2-pyridone disolved in 35 ml. of glacial acetic acid isadded .2 g. of platinum oxide. The reaction mixture is reduced underhydrogen at room temperature and 40 p.s.i. It is then filtered andconcentrated in vacuo and the residue chromatographed using silica gel,eluted with ether/ petroleum ether. The product obtained is5-(o-tolyl)-2-piperidone.

1 5 EXAMPLE 6A When an equimolar amount of the 2-pyridones from Example5A are used in place of S-(o-toIyD-Z-pyridone of Example 6, there areobtained the corresponding 2- piperidones. In this way there areobtained:

The following representative examples illustrate the interconversion orintroduction of functional groups at various stages of the preparationof the final products.

EXAMPLE 7 5 (p-nitrophenyD-Z-piperidoue To 4 ml. of ice cold sulfuricacid is added 1.75 g. of 5-phenyl-2-piperidone. To this is added amixture of 0.7 ml. nitric acid in 1 ml. cold sulfuric acid over a 40-minute period. This is then stirred for 2 hours and allowed to stand atroom temperature for 15 hours. This is then added to 100 ml. ofice-water, filtered, washed with water until the wash water is neutraland sucked dry and recrystallized from dimethoxyethane to obtain5-(pnitrophenyU-Z-piperidone.

EXAMPLE 8 5- (p-aminophenyl) -2-piperidone5-(p-nitrophenyl)-2-piperidone (1 g.) is reduced in 50 ml. of warmdioxane under a hydrogen atmosphere in the presence of 0.3 g. of 5%palladium-on-carbon. The mixture is filtered, washed with warm dioxane,and the combined filtrates concentrated in vacuo to obtain5-(paminophenyl) -2-piperidone.

EXAMPLE 9 1-methyl-5-(p-dimethylaminophenyl)-2-piperidonel-methyl-S-(p-nitrophenyl)-2-piperidone (1 g.) is reduced in 100 ml. ofmethanol containing 1 ml. of glacial acetic acid and 3 ml. of 37%formaldehyde in the presence of A teaspoonful of Raney nickel under ahydrogen atmosphere. The mixture is filtered and washed with methanoland concentrated in vacuo. Chromatography on an alumina column usingmethanol-methylene chloride system (v./v. -100%) yieldsl-methyl-S-(p-dimethylaminophenyl)-2-piperidone.

EXAMPLE 1O (p-hydroxyphenyl) -2[ 1H] pyridone5-(p-methoxyphenyl)-2[IHJpyridone (2 g.) is added to a stirred 10 g.portion of pyridine hydrochloride at 188 C. A dry nitrogen atmosphere ismaintained. The mixture is kept 20 minutes, allowed to cool, then addedto 45 g. of ice. The crude product is collected, dried, andchromatographed using methanol/methylene chloride (0- 100%) to obtain 5-(p-hydroxyphenyl)-2[1H]-pyridone.

16 EXAMPLE 11 5-(o-methylphenyl)-2-thiopiperidone To 20.8 g. (0.11 mole)of 5-(o-methylphenyl)-2-piperidone in 75 ml. of dry pyridine is added 13g. (0.058 mole) phosphorus pentasulfide suspended in 75 ml. of drypyridene. The reaction mixture is refluxed for /2 hour. The pyridine isremoved in vacuo and the residue pumped dry at room temperature forseveral hours. The residual black tar is extracted in a Soxhlet with1500 ml. benzene and the benzene then evaporated to dryness. The residueis recrystallized from methanol to obtain5-(o-methylphenyl)-2-thiopiperidone.

EXAMPLE 12 When an equimolar amount of each of the two piperidones ofExample 2 are used in place of 5-(o-methyl phenyl)-2-piperidone, thecorresponding 2-thiopiperidone is prepared.

5-(p-chlorophenyl)-2-thiopiperidone 5-phenyl-2-thiopiperidone5-(p-fluorophenyl)-2-thiopiperidone 5-(o-chlorophenyl)-2-thiopiperidone5-(rn-chlorophenyl)-5-carboethoxy-Z-thiopiperidone5-(p-methoxyphenyl)-2-thiopiperidoneS-(p-trifluoromethylphenyl)-2-thiopiperidone5-(p-aminophenyl)-2-thiopiperidone5-(p-dimethylaminophenyl)-2-thiopiperidoneS-(p-methylaminophenyl)-2-thiopiperidone5-(p-biphenylyl-S-methy1-2-thiopiperidoneS-(p-nitrophenyl)-2-thiopiperidone 5-(a-naphthyl)-2-thiopiperidone5-(o-methylphenyl)-2-thiopiperidone 5 p-hydroxyphenyl) -2-thiopiperidone5-(2,6-dichlorophenyl)-2-thiopiperidoneS-(p-carbomethoxyphenyl)-5-phenyl-2-thiopiperidone 5- (p-carb oxyphenyl)-2-thiopiperidone 5-(p-dimethylsulfamylphenyl)-2-thiopiperidone5-(2-methyl-4-chlorophenyl)-2-thiopiperidone5-(3,4-dimethoxyphenyl)-2-thiopiperidoneS-methyl-S-phenyl-Z-thiopiperidone3-methyl-5-(o-methylphenyl)thiopiperidone 3-methyl-5- (p-chlorophenyl)thiopiperidone 3-methyl-5-(2,6-dichlorophenyl)thiopiperidone3,4-dimethyl-5-(o-methylphenyl)thiopiperidone3-chloro-5-(p-chlorophenyl)thiopiperidone3-amino-5-phenyl-2-thiopiperidone3-dimethylamino-5-phenyl-2-thiopiperidone3-dimethylaminoethyl-5-pheny1-2-thiopiperidone4-phenyl-5-(o-methylphenyl)-2-thiopiperidone3-phenyl-5-(o-methylphenyl)-2-thiopiperidone3-hydroxy-5-(p-hydroxyphenyl)-2-thiopiperidone3-methyl-5-(p-nitrophenyl)-2-thiopiperidone3,4-dimethyl-5-(p-chlorophenyl)-2-thiopiperidone3,4-dimethyl-5-(o-methylphenyl)-2-thiopiperidone3-methyl-5-(2,6-dichlorophenyl)-2-thiopiperidone3-methyl-5-(p-methoxyphenyl)-2-thiopiperidone3-methyl-5-(2-methyl-4-chlorophenyl)-2-thiopiperidone3,4-dimethyl-5-(p-biphenylyl)-2-thiopiperidone3,4-dimethyl-5-(o-chlorophenyl)-2-thiopiperidone3-methyl-5-(3,4-dimethoxyphenyl)-2-th.iopiperidone EXAMPLE 135-(p-chlorophenyl)-l-benzyl-Z-thiopiperidone To 27.9 g. of5-(p-ch1orophenyl)-l-benzyl-2-piperidone in 75 m1. of dry pyridine isadded 13 g. (0.058 mole) phosphorus pentasulfide suspended in 75 m1. ofdry pyridine. The reaction mixture is refluxed for /2 hour. The pyridineis removed in vacuo and the residue pumped dry at room temperature forseveral hours. The residual black tar is extracted in a Soxhlet with1500 ml. benzene and the benzene then evaporated to dryness. The residueis recrystallized from methanol to obtain S-(p-chlorophenyl)Jbenzyl-Z-thiopiperidone.

17 EXAMPLE 14 When an equimolar amount of each of the'2-pipericlones ofTable II, =Example 3A and Table III, Example 3B, are used in place ofthe S-(p-chlorophenyl)-1-benzyl- 2-thiopiperidone in Example 13, thenthe corresponding 2-thiopiperidone is prepared.

5- (p-chlorophenyl lmethyl-2-thiopiperidone 5- p-chlorophenyl) -l-Z-butenyl -2-thiopiperid0ne 5- p-chlorophenyl 1- (4-pentenyl-2-thiopiperidone 5- (p-chlorophenyl) -1-methallyl-2-thiopiperidone5-(p-chloropheny1) -1-( 3-pentynyl) -2-thiopiperidone 5- (p-chlorophenyl1-benzyl-2-thiopiperidone 5- (p-chlorophenyll-phenethyl-2-thiopiperidone 5- (p-chlorophenyl-1-phenyl-2-thiopiperidone S-(p-chlorophenyl) -1- (3-phenyl-2-propenyl)-2-thiopiperidone 5- (p-chlorophenyl)-1-diethylaminoethyl-Z-thiopiperidone 5-phenyl-1-(2-propenyl)-2-thiopiperidone 5 -phenyl-l-benzyl-2-thiopiperidone 5 -phenyl-1-methallyl-2-thiopiperidone 5-phenyl-1-(3-phenyl-2-propenyl) -2-thiopiperidone 5-phenyl-1-(2-butenyl) -2-thiopiperidone 5 -phenyl- 1-diethylaminoethyl-2-thiopiperidone 5 -phenyll-phenyl-Z-thiopiperidone5- o-methylphenyl -1-methallyl-Z-thiopiperidone 5- 2,6-dichlorophenyl) l-methallyl-3 -chloro-2-thiopiperidone 5- (p-fiuorophenyl)-1-diethylaminoethyl-Z-thiopiperidone 5- u-naphthyll-methyl-Z-thiopiperidone 5- o-methylphenyl1-acetyl-4-chloro-2-thiopiperidone 5 (o-methylphenyl)l-methyl-4-methyl-2-thiopiperidoneS-phenyll-acetyl-3-methyl-2-thiopiperidone 5-phenyl-1-acetyl-3-dimethylamino-2-thiopiperidone 5- p-nitrophenyl-l-benzyl-3,4-dirnethyl-Z-thiopiperidone 5- o-methylphenyl)-1phenyl-2-thiopiperidone The invention is further demonstrated by thefollowing examples in which all parts are by weight.

EXAMPLE 15 A mixture of 250 parts of S-(p-nitrophenyl)-2-piperidone and25 parts of lactose is granulated with suitable Water, and to this isadded 100 parts of maize starch. The mass is passed through a 16 meshscreen. The granules are dried at a temperature below 60 C. The drygranules are passed through a 16 mesh screen, and mixed with 3.8 partsof magnesium stearate. They are then compressed into tablets suitablefor oral administration.

The piperidone used in the foregoing example may be replaced by 25, 100or 500 parts of other piperidones or thiopiperidones of this inventionto produce tablets suitable for oral administration as anantiinflammatory, antipyretic and/r analgesic according to the method ofthis invention.

EXAMPLE 16 A mixture of '50 parts of -(p-chlorophenyl)-2-piperidone, 3parts of the calcium salt of lignin sulphonic acid, and 237 parts ofwater is ball-milled until the size of substantially all of theparticles of the piperidone is less than microns. The suspension isdiluted with a solution containing 3 parts of sodiumcarboxymethylcellulose and 0.9 parts of the butyl ester ofp-hydroxybenzoic acid in 300 parts of water. There is thus obtained anaqueous suspension suitable for oral administration for therapeuticpurposes.

EXAMPLE 17 A mixture of 250 parts of 5-(o-tolyl)-2-piperidone, 200 partsof maize starch and 30 parts of alginic acid is mixed with a sufiicientquantity of 10% aqueous maize starch, and granulated. The granules aredried in a current of warm air and the dry granules are then passedthrough a 16-mesh screen, mixed with 6 parts of magnesium stearate andcompressed into tablet form to obtain tablets suitable for oraladministration.

18 EXAMPLE 1s A mixture of 500 parts of the thiopiperidone of Example15, 60 parts maize starch and 20 parts of gum acacia is granulated witha suflicient quantity of water. The mass is passed through a 12-meshscreen and the granules are dried in a current of warm air. The drygranules are passed through a 16-mesh screen, mixed with 5 parts ofmagnesium stearate and compressed into tablet form suitable for oraladministration.

EXAMPLE 19 1) Tablets.-l0,000 scored tablets for oral use, eachcontaining 500 mg. of piperidone are prepared from the followingingredients:

Gm. S-(p-aminophenyl)-2-piperidone 5000 Starch, U.S.P. 350 Talc, U.S.P.250 Calcium stearate 35 Gm. 5-(p-methoxyphenyl)-2-piperidone 2500Lactose, U.S.P. 1000 Starch, U.S.P. 300 Talc, U.S.P. 65 Calcium stearate25 The powdered piperidone is mixed with the starchlactose mixturefollowed by the tale and calcium stearate. The final mixture is thenencapsulated in the usual manner. Capsules containing 10, 25, 50 and mg.of piperidone are also prepared by substituting 100, 250, 500 and 1000gm. for 2500 gm. in the above formulation.

(3) Soft elastic capsules.-One-piece soft elastic capsules for oral use,each containing 200 mg. of piperidone are prepared in the usual mannerby first dispersing the powdered active material in sufiicient corn oilto render the material capsulatable.

' (4) Aqueous suspension-An aqueous suspension for oral use containingin each 5 ml., 1 gram of piperidone is prepared from the followingingredients:

Deionized water, q.s. to 10,000 mg.

What is claimed is: 1. A compound of the formula:

where References Cited A is 0 or S; Hill et al., J.A.C.S. sum-739 1959 Ris hydrogen, loweralkyl, phenyl, benzyl or loweralkynyl; I

d HENRY R. JILES, Primary Examiner Y is chloro, nitro, amino ordiloweralkylamino. 5 s, WINTERS, Assistant Examiner 2. A compoundaccording to claim 1 where R is hydrogcn; and Y is p-nitro. US. Cl. X.R.

3. A compound according to claim 1 where R is 2 0 293 7 293,77, 465 D,471 A, 297 z, 290 HL, hydrogen; and Y is p-chloro. 10 465 F, 465 G, 465E; 424-267

